Rectal dose to prostate cancer patients treated with proton therapy with or without rectal spacer

Abstract The purpose of this study was to evaluate whether a spacer inserted in the prerectal space could reduce modeled rectal dose and toxicity rates for patients with prostate cancer treated in silico with pencil beam scanning (PBS) proton therapy. A total of 20 patients were included in this study who received photon therapy (12 with rectal spacer (DuraSeal™ gel) and 8 without). Two PBS treatment plans were retrospectively created for each patient using the following beam arrangements: (1) lateral‐opposed (LAT) fields and (2) left and right anterior oblique (LAO/RAO) fields. Dose volume histograms (DVH) were generated for the prostate, rectum, bladder, and right and left femoral heads. The normal tissue complication probability (NTCP) for ≥grade 2 rectal toxicity was calculated using the Lyman–Kutcher–Burman model and compared between patients with and without the rectal spacer. A significantly lower mean rectal DVH was achieved in patients with rectal spacer compared to those without. For LAT plans, the mean rectal V70 with and without rectal spacer was 4.19 and 13.5%, respectively. For LAO/RAO plans, the mean rectal V70 with and without rectal spacer was 5.07 and 13.5%, respectively. No significant differences were found in any rectal dosimetric parameters between the LAT and the LAO/RAO plans generated with the rectal spacers. We found that ≥ 9 mm space resulted in a significant decrease in NTCP modeled for ≥grade 2 rectal toxicity. Rectal spacers can significantly decrease modeled rectal dose and predicted ≥grade 2 rectal toxicity in prostate cancer patients treated in silico with PBS. A minimum of 9 mm separation between the prostate and anterior rectal wall yields the largest benefit.

In order to maximize the therapeutic benefit of dose escalation to the prostate, the use of a tissue spacer to increase the physical distance between the prostate and the rectum has been studied [18][19][20][21][22] in order to minimize rectal toxicities. Recently, Mariados et al. 18 reported a significant reduction in the volume of the rectum receiving 70 Gy or more (V70) from 12.4 to 3.3% (P < 0.01), for patients treated with image-guided intensity modulated radiation therapy (IMRT), planned pre-and postspacer.
Proton therapy has advantageous dose deposition properties resulting in a decrease in the volume of normal tissues irradiated compared to photon irradiation. Proton therapy has been delivered in the past using a passive system (passive scattering), but a more conformal and highly modulated beam can be created using actively scanned proton beamlets (PBS) that are overlaid over the target volume. 23 Proton therapy has become an increasingly utilized treatment for patients with prostate cancer, [24][25][26][27] and a large number of PBS proton therapy centers are scheduled to open in the next 5 yr.
Recent retrospective reviews have cast doubt on the value of proton therapy for the treatment of prostate cancer, with some studies suggesting low rates of rectal toxicity compared to IMRT, while other suggesting similar rates. 28,29 PBS proton therapy may prove to result in superior quality of life in the long run, but currently questions remain regarding its use relative to rectal toxicity.
The purpose of this study was to evaluate whether the use of a rectal spacer could reduce modeled rectal toxicity for patient undergoing in silico pencil beam scanning (PBS) proton therapy for prostate cancer, to quantify the modeled differences, and to evaluate the minimum space requirement between the prostate and rectum to yield a significant reduction in V70.

| Rectal spacer
Twelve nonmetastatic prostate cancer patients treated with definitive radiotherapy were included in this IRB-approved study. Each had DuraSeal TM gel (Covidien, Mansfield, MA, USA) inserted percutaneously through the peritoneum posterior to Denonvillier's fascia and anterior to the rectum. An ultrasound image-guided injection of the gel (5 ml) via 16-guage catheter was performed to the level of the mid prostate gland to slowly separate the anterior perirectal fat, thus creating a space for the gel at the level of the mid prostate gland. 30 The injection of DuraSeal TM gel was done prior to CT simulation by a radiation oncologist with significant brachytherapy experience (M.B. or D.F.). In this study, we refer to the DuraSeal TM gel as the rectal spacer.
The separation distance between the rectum and the prostate was measured for all patients. The measurements were taken at three points; superior, middle, and inferior aspects of the prostate gland on an axial plane using the planning CT images. The minimum separation distance in any of these three measurements was used for our analysis regarding the impact of separation distance on reduction in modeled toxicities.

| Rectal NTCP
Lyman-Kutcher-Burman (LKB) methodology was used to determine the predicted rectal toxicity rates for each beam arrangement. 32 The LKB model describes the normal tissue complication probability (NTCP) after uniform radiation of a fractional volume (v) of normal tissue to a dose (D) using the equation: TD 50 is the dose at which there is a 50% probability of developing a specified grade and type of rectal complication after uniform wholeorgan irradiation, m models the slope of the dose-response curve for this specific toxicity. The term gEUD is the generalized equivalent uniform dose which accounts for the fact that the rectum does not receive a uniform dose during treatment and is calculated according to the Kutcher-Burman histogram dose reduction method, 32 where N voxels is the number of voxels, D i is the dose to the i th voxel, and n is the volume effect factor, which models how the tolerance dose changes as the fractional volume of the rectum irradiated changes. To evaluate a minimum of grade 2 rectal toxicity, QUAN-TEC-recommended parameters were used. 33 They are as follows: , and TD 50 = 76.9 Gy (73.7 -80.1).

| Proton treatment plan evaluation
For both the LAT and LAO/RAO field arrangements, target volume coverage and critical structure planning goals were achieved for all patients regardless of the beam arrangements or the presence of a rectal spacer.

| NTCP analysis
The mean predicted rectal toxicity (G2 or higher) probabilities for patients with and without rectal spacers for LAO/RAO and LAT PBS field arrangements are summarized in Table 3 in the majority of patients having an NTCP risk of 5% or lower, suggesting that such a separation results in V70 of < 5% (Fig. 2) and this corresponds to a < 5% risk of G2 or higher rectal toxicity, an endpoint that could be useful for future clinical trials to validate.

| DISCUSSION
Our results indicate that a spacer increases the separation between the prostate and rectum, and consistently leads to marked reduction in rectal dose and predicted ≥ grade 2 rectal toxicity (Figs. 2 and 3).
This effect was not significantly different based on the use of either LAT or LAO/RAO beam arrangements. These results support those published by Christodouleas et al. who evaluated the dosimetric benefit of using a rectal spacer for prostate proton therapy in a cadaveric study. 34 In the Christodouleas et al. study, anterior and lateral beam arrangements were compared using uniform scanning and PBS. They reported that the anterior beams improved rectal dosimetric parameters when using uniform scanning, but not when using PBS. Lastly, the data in Fig. 2  both femoral heads with anterior-oriented fields. However, we did not find any difference in the volume of rectum receiving high doses (i.e., V70) for anterior-oriented fields when compared against the LAT-oriented fields. This is because the extent of rectal displacement (≥ 9 mm) was significant enough for both field arrangements to observe similar benefits of the rectal spacers to reduce the volume receiving high dose to the rectum. Consequently, while there are some potential benefits of using anterior proton beams without a rectal spacer, LAT fields should be preferred with a rectal spacer especially because they are also more robust. 25,38 A rectal spacer may also be especially beneficial for prostate cancer patients with a hip prosthesis who receive proton therapy as an anterior beam is commonly used to avoid treating through the prosthesis, and the LAO/RAO configuration would then be preferred in such situations. 39 There are several potential limitations of our study. The image dataset obtained for this study did not include CT images before and after the rectal spacer insertion because this study was conceived well after the patients had been treated. However, the study did evaluate the rectal toxicity between the 12 patients with rectal spacers and 8 patients without it. While these eight patients may be the control group (i.e., no rectal spacer), they do represent typical prostate patients for the population comparison. Also, the delineation of tissue interfaces between the rectum, prostate, and rectal spacer was challenging in some patients because of the similarity of their tissue density. To mitigate this, MRI could be used to more clearly delineate the rectal spacer although these patients did not have MRI to guide contouring. Furthermore, there were no patients with rectum-prostate separation distances between 5 and 9 mm to evaluate potential rectal toxicity in this range. This gap in the rectum-prostate separation data could influence the determination of minimum spacer thickness needed to provide maximum rectal sparing. Lastly, we did not account for the differences in the day-to-day bladder filling that could affect the dose to the rectum for the anterior oblique beams.

| CONCLUSIONS
Our modeling study suggests that a rectal spacer can significantly reduce the rectal dose and the probability of ≥grade 2 rectal toxicity among prostate cancer patients who receive PBS. Separation of at least 9 mm between the rectum and prostate may achieve optimal rectal sparing. Opposed lateral beams should be preferred over anterior oblique beams despite the presence of a rectal spacer.

CONF LICT OF I NTEREST
No conflict of interest to report.